ReviewCongenital disorders of glycosylation: Still “hot” in 2020
Introduction
Congenital disorders of glycosylation (CDG), first reported in 1980, are due to defects in the synthesis and attachment of glycoprotein and glycolipid glycans. This family of metabolic diseases is still rapidly growing since about 17% of their actual number of 137 have been reported in the last three years (see Fig. 1 for an overview picture). It is not always clear when a disease ‘merits’ the label CDG; should e.g. disorders of glycan sulfatases/desulfatases be included? Are some disorders of the glycosylphosphatidylinositol anchor biosynthesis real CDG? This is an ongoing discussion. The present review is an update on the CDG reported since 2017, and on novel CDG phenotypes (summarized in Table 1), mechanisms, markers and treatments described in this period. Finally, recent guidelines on PMM2-CDG, MPI-CDG and PGM1-CDG are summarized, followed by conclusions.
Section snippets
Disorders of N-linked glycosylation
Seven patients have been described with pathogenic variations in FUT8, a gene encoding the Golgi-localized α-1,6-fucosyltransferase essential for core N-glycan fucosylation [1,2]. Compared to the other known genetic defects affecting the process of fucosylation (SLC35C1, POFUT1, LFNG defects), the clinical presentation in FUT8-CDG patients is generally more severe, and seems to have a recognizable pattern involving severe developmental and growth delay, epilepsy, feeding difficulties with
Novel phenotypes of known CDG
Biallelic missense variants in ATP6V1A have been previously described to cause severe systemic disorder with psychomotor delay, epilepsy, progeroid facial features, cutis laxa, cardiomyopathy, strabismus and cataract with impaired glycosylation in four patients [60,61]. A recent study shows that even de novo heterozygous missense variants can be disease-causing presenting as infantile-onset epileptic encephalopathy with severe developmental delay (DD) in four patients [62]. However, the
Novel mechanisms of CDG
Multiple studies have focused on TMEM165, a Golgi-localized protein whose deficiency leads to strong glycosylation abnormalities and manifests with psychomotor delay and severe skeletal involvement [79]. It was found that TMEM165 has splice-transcript isoforms which differ in their tissue-expression profile and the effect on glycosylation, implying a regulatory function [80]. Besides its role in Golgi manganese homeostasis as a putative Mn2+ transporter [81], TMEM165 was demonstrated to rapidly
Novel diagnostic markers
Apolipoprotein C-III (ApoC-III), used as a marker for mucin type 1 O-glycan biosynthesis defects, was analyzed in a group of glycogen storage diseases (GSD; types 0, Ia, non-Ia, III and IX), and a significantly reduced ApoC-III glycosylation was found in GSD types III and IX; this could aid in the differential diagnostics due to a lack/unreliability of specific enzymatic assays for these two disorders [96]. Two-dimensional electrophoresis of haptoglobin β glycoforms was found to be a good
Novel treatments
Although the number of known CDG is rapidly growing, an effective treatment is known only for a small part of them. We are aware of a more or less effective therapy for 12 out of the 137 CDG (seven by monosaccharide substitution and five by other treatment modalities; summarized in Table 2). Organ transplantation and other treatment modalities are known to ameliorate certain clinical aspects of 13 other CDG. In vitro experiments are testing other options.
Clinical guidelines
In the last years, guidelines have been established for the diagnosis and clinical management of the most common CDG.
The PMM2-CDG guidelines include complex information about the natural course and recommendations for surveillance and clinical management. The data review of 595 published patients showed that the most common symptoms are neurological (ID in 96%, cerebellar ataxia and atrophy in 96%, hypotonia in 92% and peripheral neuropathy in 53%), skeletal (thoracic deformities in 84% and
Conclusions
This review is again an illustration of the remarkable heterogeneity of CDG. As seen previously, also this sample of 23 CDG shows in the large majority (76%) neurological involvement associated with other organ disease. It also confirms that a CDG can be a mono-organ disease (PIGH-CDG: brain, VMA21-CDG: liver, CSGALNACT1-CDG and TRIP11-CDG: skeleton) and that a number of CDG appear to be ‘chameleon diseases’ (COG4-CDG, COG8-CDG, POFUT1-CDG, among others). Not only are CDG unique because they
Funding information
The work was supported by Ministry of Health, Czech Republic - conceptual development of research organization: Grant No. MH CZ-DRO – VFN64165, by Ministry of Education, Youth and Sports of Czech Republic Grant No. 8F19002 (under the frame of E-Rare-3, the ERA-Net for Research on Rare Diseases) and by Progres Q26/LF1 Programs of the Charles University.
Authors' contributions
Nina Ondruskova and Anna Cechova conducted the review and wrote a substantial part of the manuscript including the figure and tables. Jaak Jaeken and Tomas Honzik wrote parts of the manuscript and contributed with advice and critical comments. Hana Hansikova supervised the manuscript preparation. The manuscript was reviewed and revised by all the authors.
Declaration of Competing Interest
No competing interest.
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- 1
The first two authors contributed equally to this work.
- 2
The last two authors contributed equally to this work.